Treatment of Genetic Disorders

1. Treatment of Genetic Disorders DrMaha Al-Sulaimani Department of Biochemistry College of Sciences

2. Current Therapy of Genetic Disorders • Preventive. • Metabolic Manipulation. • Gene Product Replacement. • Cell or Organ Transplantation. • Gene Therapy.

3. Therapy of Genetic Disorders • Preventive Therapy: • Prenatal Diagnosis (amniocentesis, chorionic vallussampling, panorama test and ultrasound). • PreimplantationDiagnosis. (in vitro fertilization, testing of embryo & implantation of normal embryo). -Newborn Screening.

4. Therapy of Genetic Disorders • Metabolic Manipulation: • Dietary restriction: • (Lactose restriction for Lactase deficiency; phenylalanine restriction for phenylketonuria). • Dietary Supplementation: • (Vitamin C for Scurvy, Starch for G-6-P deficiency). • Chelation and enhanced excretion: • (Copper chelation for Wilson`s Disease). • Metabolic inhibitors: • (Allopurinol for gout, Statins for hypercholesterolemia).

5. Therapy of Genetic Disorders • Gene Product Replacement Therapy: • Hormone, protein or enzyme replacement: • Hormone supplementation: • Hypothyroidism: thyroxine. • Congenital adrenal hyperplasia: cortisol. • Growth hormone. • Hemophilia: clotting factors. • Diabetes: insulin. • Enzyme replacement: • Acid Beta glucosidase : Gaucher`s disease (lysosome storage disease), glucocerebroside accumulates in the macrophage-monocyte system). • Alpha glucosidase: Pompe.

6. Cells Bone marrow Immunodeficiency Disorders. Organs KidneyFabry`s Disease (lysosomal storage disease): - galactosidase: glycolipid accumulation in blood vessels). LiverTyrosinemia. Therapy of Genetic Disorders • Cell or Organ Transplantation

7. Definition of Gene Therapy • Gene therapy is the insertion of genes into an individual`s cells and tissues to treat a disease, such as a hereditary disease in which a deleterious mutant allele is replaced with a functional one. • Although the technology is still in it`s infancy, it has been used with some success.

8. Gene Therapy: How It Works • A vector delivers the therapeutic gene into a patient`s target cell. • The target cells become infected with the viral vector. • The vector`s genetic material is inserted into the target cell. • Functional proteins are created from the therapeutic gene causing the cell to return to a normal state.

9. What Gene therapy can achieve • Replacing a mutated gene that causes disease with a healthy copy of the gene. • Inactivating or “knocking out” a mutated gene that is functioning improperly. • Introducing a new gene into the body to help fight a disease.

10. Antisense Therapy • Antisense therapy is a form of treatment for genetic disorders or infections. • When the genetic sequence of a particular gene is known to be causative of a particular disease, it is possible to synthesize a strand of nucleic acid (DNA or RNA or a chemical analogue) that will bind to the mRNA produced by that gene and inactivate it, effectively turning the gene “off”.

11. Antisense Therapy • Antisense therapy is not strictly a form of gene therapy, but is a genetically-mediated therapy and is often considered together with other methods.

12. Gene Therapy • Gene therapy is being studied in clinical trials for different types of cancer. • It is currently not available outside clinical trials.

13. Disease Characteristics Currently Ideal for Gene Therapy • Lethal disorder. • Course not highly variable. • Reversible. • No universal therapy. • Gene cloned. • No tissue specificity or regulation. • Bone marrow cells involved.

14. Gene Therapy: Types • Introduction of a normal gene: • Somatic. • Germ line. • Therapy of non-inherited disorders: • (Cancer, AIDS).

15. Somatic Gene Therapy -Introduction of recombinant genes into somatic cells to treat genetic or acquired disease. • Does not involve germ line. • Applicable to any disease with known molecular basis of pathogenesis. • Currently does not involve removal, repair or site-specific replacement of mutant genes. • May not require permanent alteration of cells (repetitive therapy).

16. Reversion of mutation to normal Normal cells Mutant cells Somatic Mosaicism: Reversion of an Inherited Mutation to Normal and Selective Growth Advantage Mutant

17. Germ-line Gene Therapy • Germ cells, i.e., sperm or eggs, are modified by the introduction of functional genes, which are integrated into their genomes. • This would allow the therapy to be heritable and passed on to later generations. • Although this should, in theory, be highly effective in counteracting genetic disorders and hereditary diseases, many jurisdictions prohibit this for application in human beings, at least for the present, for a variety of technical and ethical reasons.

18. State of the Art of Genetic Engineering • Ideal: • Replace defective gene with normal one (site specific insertion). • Target vector containing the gene to damaged cell. • In vivo administration is safe, effective and permanent (integration into DNA but not at oncogenic sites). • Vector contains all regulatory elements. • Current: • Site specific insertion very early and experimental. • No current trial incorporates all of the ideal requirements.

19. “Successful” Gene Therapy for Immunodeficiency Diseases: 2005 • Over 14 patients with X-linked severe combined immunodeficiency of 3 different types have been treated successfully. • Oncogenic insertion in two of 14 children with leukemia.